Bioactive components from the stem bark of the paw paw tree, Asimina triloba (Annonaceae)
Abstract
The objective of this project has been to find highly potent, novel, acetogenins from Annonaceous plants. The current bioactivity-directed phytochemical investigation of the EtOH extract of the paw paw tree, Asimina triloba (L.) Dunal (Annonaceae) has resulted in the isolation of twenty-three bioactive components; fourteen of these Annonaceous acetogenins (2-7, 9, 12, 13, 15-19) are new to the literature; nine known acetogenins (8, 10, 11, and 13) and non-acetogenic compounds (20-23) are reported, for the first time, from this species. The structures of the novel acetogenins were determined by spectral analyses including UV, IR, CIMS, EIMS, FABMS, 1D-NMR, and 2D-NMR experiments (COSY, relayed COSY, HMQC, HMBC, and NOESY); as well as chemical derivative preparations. The relative stereochemistries between the methine protons around the THF rings were established by the NMR spectral comparisons of these natural products with the synthetic model compounds. The absolute configurations of the carbinol centers were established by Mosher ester methods. The most interesting findings, in this respect, were trilobacin (15) and trilobin (16) which are the first reported adjacent bis-THF acetogenins with a threo/trans/erythro/cis/threo relative configuration; and, thus, these represent a new stereochemical type of adjacent bis-THF subunit. All of the isolated natural compounds showed significant activity in the brine shrimp bioassay (BST) and in human solid tumor cell line tests (A-549, MCF-7, HT-29) with ED$\sb{50}$ values as low as ${<}10\sp{-12}\ \mu$g/ml. The adjacent bis-THF acetogenins are the most potent components and exhibited, in the human colon tumor cell line (HT-29), nearly one billion times the activities of the mono-THF acetogenins, the non-acetogenic compounds, and the standard reference, adriamycin. The distant hydroxylations, at positions C-10, 28, 29, and 30 are important for the enhancement of activities. These hydroxylation isomers represent the optimum structural activity relationships for this series of compounds.
Degree
Ph.D.
Advisors
McLaughlin, Purdue University.
Subject Area
Pharmaceuticals|Pharmacology|Analytical chemistry
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